Metabolic improvement in patients with acid sphingomyelinase deficiency following intravenous trehalose administration: an untargeted pharmacometabolomic study

Acid sphingomyelinase deficiency (ASMD) A and B, historically known as Niemann-Pick (NP) types A (NPA) and B (NPB), are life-threatening and rare inherited lysosomal storage disorders, caused by a deficiency in the acid sphingomyelinase enzyme activity. The negative outcome of this deficiency is the sphingomyelin (SM) accumulation in different organs and tissues. Trehalose is a natural disaccharide with neuroprotective and autophagy-inducing abilities that has recently been shown to improve clinical and biochemical features of patients with ASMD A/B. We previously showed that trehalose can reduce the serum levels of sphingomyelins and improve disease symptoms caused by lipid accumulation in ASMD A/B patients. The aim of this study was to investigate the serum metabolome changes in five patients with ASMD A/B, who received 15 g/week of trehalose intravenously for three months, using an untargeted gas chromatography-mass spectrometry (GC-MS) method. GC-MS technique was used to assess the serum metabolic profile of patients with ASMD A/B. MSDIAL was used for data processing, and multivariate data analysis including Principal Component Analysis (PCA), and Orthogonal projections to latent structures discriminant analysis (OPLS-DA) algorithms were carried out using SIMCA. OPLS-DA model revealed significant changes in several serum metabolites including phosphate (P = 0.0019), sorbitol (P = 0.00009), myoinositol (P = 0.02), threonine (P = 0.01), lactic acid (P = 0.0001), 1-monopalmitin (P = 0.01), threitol (P = 0.002), ribitol (P = 0.008), and D-ribose (P = 0.007) following trehalose treatment. The findings revealed that the beneficial effects of trehalose in patients with ASMD might be mediated by metabolic alterations. A clear shift in glucose metabolism in favor of less fatty acid production together with facilitating the breakdown of sphingomyelins is involved in the observed protective activity.